Herpes Simplex Virus type 1 Inflammasome Activation in Human Macrophages is Dependent on NLRP3, ASC, and Caspase-1

Abstract

20 Review and Editing 21 22 23 Abstract:24 The pro-inflammatory cytokines interleukin (IL)-1 and IL-18 are products of activation of the 25 inflammasome, an innate sensing system, and important in the pathogenesis of herpes simplex 26 type 1 (HSV-1). The release of IL-18 and IL-1 from monocytes/macrophages is critical for 27 protection from HSV-1 based on animal models of encephalitis and genital infection, yet if and 28 how HSV-1 activates inflammasomes in human macrophages is unknown. To investigate this, 29 we utilized both primary human monocyte derived macrophages and human monocytic cell 30 lines (THP-1 cells) with various inflammasome components knocked-out. We found that HSV-1 31 activates inflammasome signaling in pro-inflammatory primary human macrophages.32 Additionally, HSV-1 inflammasome activation is dependent on nucleotide-binding domain and 33 leucine-rich repeat-containing receptor 3 (NLRP3), apoptosis-associated speck-like molecule 34 containing a caspase recruitment domain (ASC), and caspase-1, but not on absent in melanoma 35 2 (AIM2), or gamma interferon-inducible protein 16 (IFI16). Ultraviolet irradiation of HSV-1 36 enhanced inflammasome activation, demonstrating that viral replication suppresses 37 inflammasome activation. These results confirm that HSV-1 is capable of activating the 38 inflammasome in human macrophages through an NLRP3 dependent process and that the virus 39 has an NLRP3 specific mechanism to inhibit inflammasome activation in monocytes and 40 macrophages. 41 42 43 44 3 45 Author Summary: 46The inflammasome is a multi-protein complex that forms in response to pathogens and 47 cellular damage. Active inflammasomes recruit pro-caspase-1 via ASC and cleave the cytokine 48 precursors pro-IL-1 and pro-IL-18 into mature IL-1 and IL-18. These cytokines serve to 49 activate other immune cells that either repair the damage or attempt to clear the invading 50 pathogen. Upon activation, the inflammasome also promotes an inflammatory form of cell 51 death called pyroptosis. Herpes simplex virus type 1 (HSV-1) is a common human pathogen that 52 can cause cold sores, genital ulcers, encephalitis, and blindness. HSV-1 infection leads to 53 induction of IL-1 and IL-18, but whether it is capable of activating inflammasomes in 54 macrophages, which play a role in severe forms of HSV-1 infection, was unclear. Here, we 55 infected both primary human macrophages and a macrophage/monocytic cell line, THP-1 cells, 56 with HSV-1. We found that HSV-1 does activate inflammasome signaling in macrophages in a 57 process dependent on NLRP3, ASC, and caspase-1. This is important because it illustrates the 58 mechanism by which HSV-1 infection leads to inflammasome activation in macrophages, known 59 to be crucial for protection from severe disease in mouse models. 60 61 62 63 64 65 66 4 67 Introduction: 68 The ability to quickly recognize and respond to pathogens is essential to host survival. 69 The first opportunity to do so lies in the innate immune response. One of the most essential 70 aspe...

Transcriptome analysis reveals dysregulation of immune and inflammatory responses in DRG and spinal cord of a mouse model of acute herpetic neuralgia

“…Although it is unclear which cell type in DRG and spinal cord was infected by HSV-1. Infection of sensory neurons with HSV-1 results in the in ltration of macrophages and mononuclear cells into DRG and the release of in ammatory mediators such as cytokines [51][52][53]. Moreover, it is known that CCR5 regulates the expression of cytokines [41,42].…”